Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential.
Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
Kränkel
Nicolle
N
Experimental Cardiovascular Medicine, Bristol Heart Institute, UK.
Katare
Rajesh G
RG
Siragusa
Mauro
M
Barcelos
Luciola S
LS
Campagnolo
Paola
P
Mangialardi
Giuseppe
G
Fortunato
Orazio
O
Spinetti
Gaia
G
Tran
Nguyen
N
Zacharowski
Kai
K
Wojakowski
Wojciech
W
Mroz
Iwona
I
Herman
Andrew
A
Manning Fox
Jocelyn E
JE
MacDonald
Patrick E
PE
Schanstra
Joost P
JP
Bascands
Jean Loup
JL
Ascione
Raimondo
R
Angelini
Gianni
G
Emanueli
Costanza
C
Madeddu
Paolo
P
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000787:Angina Pectoris / Q000503:physiopathology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology / Q000637:transplantation*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D000318:Adrenergic beta-Agonists; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin